Von willebrand factor or factor viii and von willebrand factor for the treatment of coagulopathy induced by inhibitors of thrombocytes

ABSTRACT

The present invention relates to a von Willebrand Factor for use in the treatment and/or prevention of a bleeding event associated with a thrombopathy induced by substances inhibiting thrombocytes. Furthermore, the present invention relates to a method of treating and/or preventing a disorder related to a bleeding event associated with a thrombopathy induced by substances inhibiting thrombocytes comprising administering a pharmaceutically effective amount of a von-Willebrand-Factor (vWF) to a patient in need thereof. The present invention also relates to a composition comprising vWF and a composition comprising FVIII for simultaneous, separate or sequential use for use in the treatment and/or prevention of a bleeding event associated with a thrombopathy induced by substances inhibiting thrombocytes.

The present invention relates to a von Willebrand Factor for use in thetreatment and/or prevention of a bleeding event associated with athrombopathy induced by substances inhibiting thrombocytes. Furthermore,the present invention relates to a method of treating and/or preventinga disorder related to a bleeding event associated with a thrombopathyinduced by substances inhibiting thrombocytes comprising administering apharmaceutically effective amount of a von-Willebrand-Factor (vWF) to apatient in need thereof. The present invention also relates to acomposition comprising vWF and a composition comprising FVIII forsimultaneous, separate or sequential use for use in the treatment and/orprevention of a bleeding event associated with a thrombopathy induced bysubstances inhibiting thrombocytes.

In this specification, a number of documents including patentapplications and manufacturer's manuals are cited. The disclosure ofthese documents, while not considered relevant for the patentability ofthis invention, is herewith incorporated by reference in its entirety.More specifically, all referenced documents are incorporated byreference to the same extent as if each individual document wasspecifically and individually indicated to be incorporated by reference.

An imbalance of the components of the coagulation or the fibrinolyticsystem will manifest clinically either in thrombosis or hemorrhage,respectively. Both pathological situations can be life-threatening.After a thrombotic event, e.g. during acute myocardial infarction, itwill be tried to intervene into the actual lysis and coagulationbalance. The fibrinolytic system will be supported e.g. byadministration of Streptokinase (SK) or plasminogen activators (t-PA,uPA) to dissolve the existing blood clot. The thrombocyte activation isinhibited or reduced by thrombocyte inhibitors. Thereby the vesselsclosed by a thrombus will be recanalized and the formation of a newthrombus will be prevented. Inhibitors of the thrombocyte functions canact at different sites. Inhibitors of Cyclooxigenase (e.g.Acetylsalicylic acid) prevent the formation of Thromboxan A₂ (TXA₂)which is a potent activator of the thrombocyte function. Antagonists ofADP-receptors on the surface of thrombocytes (e.g. Clopidrogel,Ticlopidin) prevent the binding of the thrombocyte activator ADP to itsreceptor and prevent the activation of thrombocytes. The fibrinogenreceptor on the thrombocyte surface, Glycoprotein IIb/IIIa (GPIIb/IIIa), induces the aggregation of thrombocytes after the binding ofits agonist fibrinogen (or vWF). Monoclonal antibodies against GPIIb/IIIa (e.g. Abciximab) or receptor antagonists as Eptifibatide orTirofiban also prevent the aggregation of thrombocytes.

On the other hand a certain potential to form a thrombus after a vessellesion is necessary to prevent hemorrhage at these locations. Thetherapy of potentially evolving life threatening hemorrhage during thetherapy with thrombocyte inhibitors includes discontinuation of thistherapy and the administration of coagulation enhancers. Suchcoagulation enhancers consist, among others, of partially pre-activatedcoagulation factors as in the marketed product FEIBA® (Baxter) or therecombinant coagulation factor Vila (NovoSeven®, Novo Nordisk).Primarily these coagulation enhancers result in a reduction of thetherapeutic effects of the thrombocyte inhibition. Dickneite et al.(Dickneite G, Friesen H.-J., Kumpe G, Reers M, 1996 Platelets 7,283-290, Dickneite G, Nicolay U, Friesen H.-J., Reers M, 1998 ThrombHaemost 80, 192-8) describe the use of vWF and Haemate® (CSL Behring) asa coagulation enhancer during a bleeding event induced by therecombinant thrombin inhibitor Hirudin.

A quantitative measure for the anti-coagulation and fibrinolytic effectsin the clinic are different diagnostic procedures like thethromboelastography, the thrombin generation assay, the activatedpartial thromboplastin time (aPTT) or the prothrombin time (PT). Amethod to evaluate the prevention of severe hemorrhage in experimentalsettings is the bleeding of organs after a traumatic injury (DickneiteG, Doerr B, Kaspereit F, 2008 Anesth Analg 106, 1070-7).

According to mechanistic investigations regarding the occurrence ofhaemostasis after vessel lesion, thrombocytes will bind primarily to thesubendothelial collagen fibers via the von Willebrand factor (vWF). vWFis the only factor with the capability to bind thrombocytes efficientlyat low (e.g. in the venous area) as well as with high shear rates (e.g.in the arterial, coronary region or in plaque induced stenosis ofvessels) by binding to exposed collagen (Ruggeri Z M, Seminars inHematology, 1994, 31, 229-239). The following aggregation ofthrombocytes and a subsequent retraction and contraction of theaggregated platelets by the action of thrombin induces a haemostaticplug during secondary heamostasis (Hemker HC, and Poliwoda H, 1993,1-18, Barthels M and Polidowa H, Thieme, Stuttgart, Germany).

At present vWF is the largest known plasma protein. It is a multimericglycoprotein with two biological properties. At local vessel injuries itmediates thrombocyte adhesion followed by thrombus formation and it actsas a carrier for the procoagulatory coagulation factor VIII (Ruggeri ZM,1993 Current Opinion in Cell Biology, 5, 898-906). vWF is found incertain amounts in a factor VIII-free form in the subendothelial cellsand will be stored in a factor VIII-free form in the α-granula of thethrombocytes. Thrombocytes have two receptors for vWF: first GP Ib inthe GP Ib-IX-V complex and second GP IIb-IIIa (Ruggeri Z M, 1994Seminars in Hematology 31, 229-239). Via its first receptor vWF inducesa thrombocyte adhesion at the side of the vessel injury, which isfollowed by vWF and/or fibrinogen binding to the GP IIb/IIIa receptorand supports the subsequent aggregation of thrombocytes. According tothis background it is discussed in the literature to use inhibitors forthe binding of vWF as a principle for an anticoagulant drug (AlevriadouB R, Moake J L, Turner N A, Ruggeri Z M, Folie B J, Phillips M D,Schreiber A B, Hrinda M E, McIntire I V, 1993, Blood 81, 1263-1276M;Grainick H R, Williams S, McKeown L, Kramer W, Krutzsch H, Gorecki M,Pinet A Garfinkel L I, 1992 Proc. Natl. Acad. Sci. USA, 89, 7880-7884).

There is still a high medical need to diminish or prevent the adverseevents of hemorrhage after the administration of thrombocyte inhibitors.Therefore the technical problem underlying the present invention is theprovision of means and methods for successfully treating a bleedingevent caused by the administration of substances inhibitingthrombocytes.

The solution to this technical problem is achieved by providing theembodiments characterised in the claims.

Surprisingly it is found that the adverse events of bleeding orhemorrhage during or after administering a substance inhibiting thethrombocytes were diminished after the administration of von Willebrandfactor (vWF). Therefore a suitable supplementation with a vWF containingpharmaceutical composition will antagonise the adverse events ofenhanced bleeding following the antithrombocytic therapy. The adverseeffects resulting of the effects of anticoagulants or fibrinolyticstherefore are diminished or prevented. To reduce the bleeding risk inpatients the vWF can be administered either prophylactically orfollowing the anti-thrombocytic treatment.

Accordingly, the present invention relates to a von-Willebrand-Factor(vWF) for treatment and/or prevention of a bleeding event associatedwith a coagulopathy, especially a thrombopathy, induced by substancesinhibiting thrombocytes.

The term “thrombopathy” in accordance with the present invention relatesto a dysfunction in the thrombocytes whereas the number of thrombocytesis normal or marginal changed. This can be seen as a distinguishingfeature to thrombocytopenia, also known as thrombopenia, whererelatively few platelets in blood are present. Regarding thrombopathythere exist a number of medicaments restricting the function(s) ofthrombocytes, e.g. acetylsalicylic acid, diclofenac, heparin, penicillinand others. Thrombopathy is also known as thrombocytopathy which term isused herein as well.

In relation to the plasmatic coagulation, the thrombocytes have twoimportant characteristics or functions: the adhesion to thesubendothelium on the one hand and the aggregation among each other onthe other hand. In accordance with the present invention the term“substances inhibiting thrombocytes” relates to substances inhibitingthe aggregation of the thrombocytes. In general, theses substances arealso known as thrombocyte-inhibitors or antiplatelet drugs or plateletaggregation inhibitors and are administered to patients to prevent thegrowth of thrombi especially in the arteries i.e. they are administeredto prevent e.g. a stroke, a myocardial infaction or another relateddisease.

Therefore, according to the invention the term “thrombopathy, induced bysubstances inhibiting thrombocytes” relates to a dysfunction in theaggregation of the thrombocytes whereas the number of thrombocytes isnormal or marginal changed. In contrast thrombocytopenia is related to adecrease of the number of thrombocytes. The thrombopathy is induced byone, two or more substances which inhibit the aggregation ofthrombocytes. Preferably these substances will inhibit thecyclooxygenase and/or the ADP receptor.

The term “thrombopathy” as used herein preferably does not includehereditary diseases like a thrombasthenia caused by a deficiency ofplatelet membrane glycoproteins (GP) IIb/IIIa (Thrombasthenia Glanzmann)or Bernard-Soulier's syndrome caused by a deficiency of GP Ib. Thethrombasthenia is an inherited abnormality of the blood plateletscharacterized especially by defective clot retraction and often byprolonged bleeding time.

The present invention further related to a method of treating and/orpreventing a disorder related to a bleeding event associated with athrombopathy induced by substances inhibiting thrombocytes comprisingadministering a pharmaceutically effective amount of avon-Willebrand-Factor (vWF) to a patient in need thereof.

In a preferred embodiment of the use of the von Willebrand Factor or themethod of the invention the vWF is used or administered in combinationwith factor VIII as a factor VIII/von-Willebrand-factor (FVIII/vWF)combination.

Preferably, the vWF or the FVIII/vWF combination is formulated in apharmaceutical composition, optionally comprising a pharmaceuticallyacceptable carrier, excipient and/or diluent.

The term “pharmaceutical composition” as used herein relates to acomposition for administration to a patient, preferably a human patient.The pharmaceutical composition envisages alternatively mixtures of vWFor a combination of vWF and FVIII. In cases where more than one compoundis comprised in the composition it is understood that none of thesecompounds has an inhibitory effect on the other compounds also comprisedin the composition.

It is preferred that said pharmaceutical composition comprises apharmaceutically acceptable carrier, excipient and/or diluent. Examplesof suitable pharmaceutical carriers, excipients and/or diluents are wellknown in the art and include phosphate buffered saline solutions, water,emulsions, such as oil/water emulsions, various types of wetting agents,sterile solutions etc. Compositions comprising such carriers can beformulated by well known conventional methods. These pharmaceuticalcompositions can be administered to the subject at a suitable dose.Administration of the suitable compositions may be effected by differentways, e.g., by intravenous, intraperitoneal, subcutaneous orintramuscular administration. It is particularly preferred that saidadministration is carried out by injection and/or delivery, e.g., to asite in the bloodstream. The dosage regimen will be determined by theattending physician and clinical factors. As is well known in themedical arts, dosages for any one patient depend upon many factors,including the patient's size, body surface area, age, the particularcompound to be administered, sex, time and route of administration,general health, and other drugs being administered concurrently.

The pharmaceutical composition according to the invention may beadministered to the patient at a dose range of 10 to 1000 units vWF perkg body weight. Alternatively, if the FVIII/vWF combination is used thedose range administered is between 5 and 400 Units FVIII per kg bodyweight and between 10 and 1000 units vWF per kg body weight.

A preferred dose range will be between 30 and 500 units vWF per kg bodyweight or alternatively for the FVIII/vWF combination a dose of 20 to200 Units FVIII and 30 to 500 units vWF per kg body weight will beadministered.

As a pharmaceutical composition comprising vWF or vWF and FVIII,respectively, used according to the invention any marketed productcomprising vWF or vWF and FVIII can be used, e.g. Haemate® P and Humate®P (CSL Behring) which contain besides vWF also FVIII, or other plasmaticvWF products or recombinantly manufactured vWF or vWF/FVIII products.

Progress can be monitored by periodic assessment. The compositions ofthe invention may be administered locally or systemically. Preparationsfor parenteral administration include sterile aqueous or non-aqueoussolutions, suspensions, and emulsions. Examples of non-aqueous solventsare propylene glycol, polyethylene glycol, vegetable oils such as oliveoil, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions orsuspensions, including saline and buffered media. Parenteral vehiclesinclude sodium chloride solution, Ringer's dextrose, dextrose and sodiumchloride, lactated Ringer's, or fixed oils. Intravenous vehicles includefluid and nutrient replenishers, electrolyte replenishers (such as thosebased on Ringer's dextrose), and the like. Preservatives and otheradditives may also be present such as, for example, antimicrobials,anti-oxidants, chelating agents, and inert gases and the like.

In another preferred embodiment of the use of the von Willebrand Factoror the method of the invention the vWF is used or administered to act asan antidote.

The term “antidote” as used in accordance with the present inventionrelates to a substance which enhances the diminished function of thethrombocytes. Therefore an antidote according to the invention is not amatter of a classical agonist/antagonist function but improves thefunction of the thrombocytes which was diminished by substancesinhibiting thrombocytes.

In a preferred embodiment of the invention the vWF or the FVIII/vWF areused or administered as a concentrate.

In another preferred embodiment the vWF or the FVIII/vWF has beenisolated from human blood plasma or is alternatively administered as arecombinant protein.

In a preferred embodiment of the use of the von Willebrand Factor or themethod of the invention the substance inhibiting thrombocytes isselected from the group consisting of a cyclooxigenase inhibitor, aninhibitor of the ADP receptor or a combination thereof. In a morepreferred embodiment the cyclooxigenase inhibitor is acetylsalicyl acidand the inhibitor of the ADP receptor is a thienopyridino derivative,preferably clopidogrel or ticlopidine. In the most preferred embodimentthe substance inhibiting thrombocytes is acetylsalicylic acid,clopidogrel or the combination acetylsalicylic acid and clopidogrel.

The present invention further related to a composition comprising vWFand a composition comprising FVIII for simultaneous, separate orsequential use for use in the treatment and/or prevention of a bleedingevent caused by the administration of substances inhibitingthrombocytes. According to this embodiment the vWF and the FVIII aretherefore used or administered in separated standard doses.

The figures show:

FIG. 1 shows the box plots of total blood loss (significance againstgroup 1 (Plavix® control)) in the rat clopidogrel model.

FIG. 2 shows the Kaplan-Meier plot of total blood loss in the ratclopidogrel model.

FIG. 3 shows the effect of Haemate® P 200 U/kg and fresh rat plateletconcentrate (1.6×10⁹ PLT/animal) on thrombin generation/thrombogram inplatelet rich plasma.

FIG. 4 shows the box plots of blood loss in pigs after theadministration of Clopidogrel/Aspirin®.

FIG. 5 shows the Kaplan-Meier plot of blood loss in pigs after theadministration of Clopidogrel/Aspirin®.

FIG. 6 shows the effect of the administration of Clopidogrel/Aspirin® onplatelet count in pigs.

Without limitation of the present invention the examples illustrate theinvention.

EXAMPLE 1

Influence of transfused rat platelets combined with a vWF and FVIIIconcentrate (Haemate® P) on the bleeding in the rat clopidogrel model

Is was investigated whether a dose of 120 and 200 U/kg Haemate® P (i.v.)in combination with freshly prepared rat platelets would reduce thebleeding in clopidogrel treated rats. Two groups of clopidogrel treatedrats received Haemate® P (120 and 200 U/kg) without platelets. The studywas designed as an open seven-armed trial with 115 rats (+60 plateletdonors). The dosing regimen is summarized in table 1.

TABLE 1 Treatment of the groups No. Treatment Dose/volume/schedule/routeN (f) 1 Isotonic saline —/1.7-2.8 mL/kg b.w./ 25 single injection (t = d2)/i.v. Isotonic saline —/1 mL/animal/ single injection (t = d 2)/i.v. 2Isotonic saline —/1.67 mL/kg b.w./ 25 single injection (t = d 2)/i.v.Fresh rat platelets 2.8-3 × 10⁹/1 mL/animal/ single injection (t = d2)/i.v. 3 Haemate ® P 120 U/kg/1.67 mL/kg b.w./ 10 single injection (t =d 2)/i.v. Fresh rat platelets 3 × 10⁹/1 mL/animal/ single injection (t =d 2)/i.v. 4 Haemate ® P 200 U/kg/2.8 mL/kg b.w./ 15 single injection (t= d 2)/i.v. Fresh rat platelets 2.8 × 10⁹/1 mL/animal/ single injection(t = d 2)/i.v. 5 Haemate ® P 120 U/kg/1.67 mL/kg b.w./ 10 singleinjection (t = d 2)/i.v. Isotonic saline —/1 mL/animal/ single injection(t = d 2)/i.v. 6 Haemate ® P 200 U/kg/2.8 mL/kg b.w./ 25 singleinjection (t = d 2)/i.v. Isotonic saline —/1 mL/animal/ single injection(t = d 2)/i.v. 7 Negative control for TGA/ 5 no Clopidogreladministration Isotonic saline 2.8 mL/kg b.w./i.v. Isotonic saline 1mL/animal/i.v.

Rat Platelets

Blood for preparation of the platelet concentrate was taken gently bypuncturing the inferior vena cava of donor rats under deep anesthesia.3.2 mL blood were mixed with 0.8 mL trisodium citrate. Blood sampleswere pooled and centrifuged at 900 RPM for 30 minutes.Platelet-rich-plasma was collected into a fresh tube and centrifugatedat 1800-2000 RPM for 15-17 minutes. The pellet was gently resuspended inTyrode HEPES+0.3% BSA. Depending on platelet yield animals received1.6−3×10⁹ washed platelets intravenous into the tail vein.

Animal Model

Platelet inhibiton/hemorrhage was induced by 2.5 mg/kg clopidogrel(Plavix®) on day 0 and day 1. Tablets were dissolved in isotonic salineand administered by gavage. On day 2 freshly prepared rat platelets weretransfused into the tail vein by a bolus. Haemate® P was administereddirectly prior to platelet transfusion. 15 minutes after administrationof platelets, blood loss was determined. The volume of total blood losswas calculated by measuring the HGB present in the saline used forsubmersion of the tail tip. The tail tip cut was performed with ascalpel knife under deep anesthesia, removing about 3 mm of the tailtip. Immediately upon lesion, the tail tip was submerged in saline, keptat the physiological body temperature of the rats using a water bath.The observation period to monitor bleeding was 30 min.

Bleeding

Blood loss was determined as the total blood loss (t=0-30 min) andanalyzed by two-sided exact Wilcoxon test, box plot and Kaplan-Meierplot. Oral treatment with clopidogrel resulted in an increased totalblood loss (FIGS. 1 and 2, table 2). FIG. 1 illustrates that total bloodloss was significantly reduced in the group receiving platelettransfusion (statistics see table 3). Total blood loss could not bedecreased by combination of platelet transfusion and Haemate® Ptreatment compared to platelets alone. However, monotherapy withHaemate® P resulted in a significant decrease in blood loss in the groupthat received a dose of 200 U/kg. No influence on blood loss wasobserved with 120 U/kg.

TABLE 2 Total blood loss (μL) Group 2 Plavix/ Group 3 Group 6 Group 1Isotonic Plavix/ Group 4 Group 5 Plavix/ Group 0 Plavix/ saline +Haemate- Plavix/ Plavix/ Haemate- Isotonic Isotonic fresh rat P ® 120U/kg + Haemate- Haemate- P ® 200 U/kg + saline saline plateletsplatelets P ® 120 U/kg P ® 200 U/kg platelets N 18 20 20 10 10 19 10Mean 103.9 1404.2 974.4 914.0 1403.5 1025.6 865.9 SD 125.5 624.3 626.9676.6 573.3 553.3 483.0 Minimum 11 265 189 42 372 81 165 Median 65 1466960 830 1532 940 852 Maximum 507 2345 2716 2259 2193 2002 1613

TABLE 3 Statistics of total blood loss (exact Wilcoxon test) Group 6Group 2 Group 3 Plavix/ Group 1 Plavix/ Plavix/ Group 4 Group 5 Haemate-Group 0 Plavix/ Isotonic Haemate-P ® Plavix/ Plavix/ P ® IsotonicIsotonic saline + fresh 120 U/kg + Haemate-P ® Haemate-P ® 200 U/kg +p-value saline saline rat platelets platelets 120 U/kg 200 U/kgplatelets Group 0 — <0.0001 <0.0001 0.0003 <0.0001 <0.0001 <0.0001 Group1 <0.0001 — 0.0231 0.0529 0.9649 0.0461 0.0278 Group 2 <0.0001 0.0231 —0.6284 0.0585 0.6940 0.7249 Group 3 0.0003 0.0529 0.6284 — 0.0821 0.46290.9397 Group 4 <0.0001 0.9649 0.0585 0.0821 — 0.1083 0.0494 Group 5<0.0001 0.0461 0.6940 0.4629 0.1083 — 0.4629 Group 6 <0.0001 0.02780.7249 0.9397 0.0494 0.4629 —

Thrombin Generation

Treatment with clopidogrel resulted in a later onset of thrombinformation and in a decrease in peak thrombin (FIG. 3). When Haemate® Pwas administered to clopigogrel treated rats an earlier onset ofthrombin formation was observed but no increase of peak thrombin.Platelet transfusion resulted in an increase in the thrombin peak.Additional or even synergistic effects were seen when platelets andHaemate® P were combined: the peak was increased and the onset ofthrombin formation was faster.

EXAMPLE 2

Time course of bleeding in pigs after the administration of Clopidogreland Aspirin and after the additional infusion of a vWF and FVIIIconcentrate (Haemate® P).

Male castrated pigs were administered over a period of three days 75 mgclopidogrel (Plavix®) daily per os via gavage. At the third dayacetylsalicylic acid (Aspirin®) was administered intravenously in a doseof 200 mg/kg. 15 minutes later an intravenous bolus of a FVIII/vWFcontaining concentrate (60 units/kg of FVIII and about 150 units/kg ofvWF) were given (treatment group, group 3, n=6). Control animalsreceived an appropriate volume of saline instead of vWF and FVIIIconcentrate (placebo group, group 2, n=4). 5 animals received neitherthe thrombocyte inhibitors nor Haemate® P treatment (group 1, negativecontrol). During the experiment the PT and aPTT were determined inplasma, the thromboelastrography and the thrombocyte aggregation wereperformed in whole blood. For the thrombin generation, a test inplatelet rich plasma was used.

The combined administration of clopidogrel and Aspirin® lead to athrombocytopathy with impaired platelet aggregation and thrombingeneration. After spleen wounding a substantial hemorrhage was caused bythe thrombocytopathy. In contrast, the plasmatic coagulation (PT, aPTT)was not influenced by clopidogrel/acetylsalicylic acid treatment. FIG. 6shows that no significant decrease of the platelet count was observedafter the administration of clopidogrel/Aspirin®, thus nothrombocytopenia has been induced.

In tables 4 and 5 as well as in FIGS. 4 and 5 it can be seen that inthis investigation a treatment with Haemate® P decreased blood losssignificantly. It has thus been shown that a concentrate containing acoagulation vWF and factor VIII was able to partly overcome thethrombocyte inhibitor induced thrombocytopathy.

TABLE 4 Blood loss (ml) after Spleen Injury Group 2 Group 3 Placebogroup Treatment group Group 1 (Plavix/Aspirin + Plavix/Aspirin +Negative control saline) Haemate ® P N 5 4 6 Mean 83.2 811.3 387.7 SD71.0 148.5 233.9 Minimum 19 616 50 Median 40 827.5 440 Maximum 178 974670

TABLE 5 Statistics of blood loss (Wilcoxon test) Comparison p-valueNegative control (Group 1) - Placebo group (Group 2) 0.0143 Negativecontrol (Group 1) - Treatment group (Group 3) 0.0285 Placebo group(Group 2) - Treatment group (Group 3) 0.0190

1-12. (canceled)
 13. A method of treating and/or preventing a bleedingevent associated with a thrombopathy induced by at least one substanceinhibiting thrombocytes in an individual in need thereof, wherein the atleast one substance comprises an ADP receptor inhibitor, the methodcomprising administering to the individual an effective amount of acomposition before, at the same time, or after administering the atleast one substance comprising the ADP receptor inhibitor, and whereinthe composition consists essentially of (a) von-Willebrand-Factor (vWF),or (b) vWF and Factor VIII (FVIII).
 14. The method of claim 13, whereinthe at least one substance inhibiting thrombocytes comprises an ADPreceptor inhibitor and a cyclooxygenase inhibitor.
 15. The method ofclaim 14, wherein the cyclooxygenase inhibitor is acetylsalicylic acid.16. The method of claim 13, wherein the ADP receptor inhibitor is athienopyridino derivative, clopidogrel, or ticlopidine.
 17. The methodof claim 13, wherein the composition consisting essentially of vWF orvWF and FVIII is administered as an antidote.
 18. The method of claim13, wherein the composition consisting essentially of vWF or vWF andFVIII is administered as a concentrate.
 19. The method of claim 13,wherein the vWF has been isolated from human blood plasma.
 20. Themethod of claim 13, wherein the vWF is recombinant.
 21. The method ofclaim 13, wherein the vWF is administered to the individual at a dose of10 to 1000 units per kg body weight.
 22. The method of claim 13, whereinthe vWF is administered to the individual at a dose of 30 to 500 unitsper kg body weight.
 23. The method of claim 13, wherein the compositionconsisting essentially of vWF is administered sequentially orsimultaneously with a composition comprising FVIII.
 24. The method ofclaim 13, wherein the vWF is administered to the individual at a dose of10 to 1000 units per kg body weight and the FVIII is administered to theindividual at a dose of 5 to 400 units per kg body weight.
 25. Themethod of claim 13, wherein the vWF is administered to the individual ata dose of 30 to 500 units per kg body weight and the FVIII isadministered to the individual at a dose of 20 to 200 units per kg bodyweight.
 26. The method of claim 13, wherein at least one of the vWF andthe FVIII has been isolated from human blood plasma.
 27. The method ofclaim 13, wherein at least one of the vWF and the FVIII is recombinant.28. The method of claim 13, wherein the composition consists essentiallyof vWF and FVIII.
 29. The method of claim 13, wherein the ADP receptorinhibitor is clopidogrel.
 30. The method of claim 13, wherein the ADPreceptor inhibitor is ticlopidine.
 31. The method of claim 13, whereinthe at least one substance inhibiting thrombocytes comprises an ADPreceptor inhibitor and a cyclooxygenase inhibitor, and wherein the ADPreceptor inhibitor is ticlopidine and the cyclooxygenase inhibitor isacetylsalicylic acid.
 32. The method of claim 13, wherein the at leastone substance inhibiting thrombocytes comprises an ADP receptorinhibitor and a cyclooxygenase inhibitor, and wherein the ADP receptorinhibitor is clopidogrel and the cyclooxygenase inhibitor isacetylsalicylic acid.